Modulation of monocytic lipopolysaccharide-induced tissue factor expression and tumor necrosis factor alpha release by estrogen and calcitriol.

Objective: Modulatory effects of estrogens on both the immune and the coagulation system are only partially understood. In severe infections high estrogen levels have been observed both in men and postmenopausal women and are associated with increased mortality. Monocyte-derived tissue factor (TF) expression can activate the coagulation system and worsen the course of severe infection. T he aim of the current study was to evaluate the in vitro effect of estrogens on differentiation, TF expression and Tumor Necrosis Factor alpha (TNFalpha) release in human monocytes.

Design: Isolated peripheral blood monocytes, MM6- and T HP-1 cells were cultured and stimulated by lipopolysaccharides (LPS) in the presence of 17beta-estradiol (E2) and/or calcitriol. Proliferative responses were evaluated by determining the proliferation rate and by cell cycle analysis. Cell surface expression of C D14 and T F was determined by flow cytometry. TNFalpha was determined by ELISA.

Results: Although calcitriol induced the expression of the differentiation marker C D14 and decreased the expression of T F in both immature monocytic cell lines and primary monocytes, the LPS stimulation of T F expression was not significantly increased in immature monocytic cells and was decreased in mature monocytes. Calcitriol-treatment increased LPS-induced TNFalpha release in MM6 cells but inhibited TNFalpha release from peripheral blood monocytes. Treatment with E2 did not alter the phenotype or cell proliferation of resting monocytic cells. However, E2-treated monocytic cells and monocytes responded to LPS by increased TF expression and decreased TNFalpha.

Conclusions: The results suggest that estrogens may modulate T F expression and cytokine production by monocytes and may thus be involved, at least in part, in the pathophysiology of acute inflammatory processes associated with high estrogen levels.